title: Gadd45 in the liver: signal transduction and transcriptional mechanisms.
abstract: Injury and growth stimulation both remarkably increase the hepatic expression of Gadd45β. In liver cancer, promoter methylation frequently silences Gadd45β, demonstrating due to a suppressive function that is often proapoptotic. This contrasts with normal hepatocytes, where Gadd45β facilitates cell survival, growth, and proliferation. Gadd45β binds MKK7-downstream of TNFα and its receptors-to prevent this kinase from activating JNK2. Hence, the Gadd45b-/- genotype increases cell injury and decreases cell proliferation during liver regeneration (i.e., compensatory growth and proliferation). Liver hyperplasia (i.e., de novo growth and proliferation) is an alternate form of growth, caused by drugs that activate the nuclear receptor, CAR. As in regeneration, the Gadd45b-/- genotype considerably slows growth during hyperplasia. However, there is no injury and the slowing occurs because Gadd45β normally binds to CAR and activates its transcriptional stimulation. Thus, Gadd45β protects the liver through two entirely different processes: binding MKK7 to block damaging signal transduction or binding CAR to coactivate anabolic transcription.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, BST South S421, 200 Lothrop Street, Pittsburgh, PA, 15261, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Tian
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration / Q000235:genetics; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D000090702:Constitutive Androstane Receptor; D048688:MAP Kinase Kinase 7; D018160:Receptors, Cytoplasmic and Nuclear; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C482569:MAP2K7 protein, human